A major controversy is playing itself out on the pages of major journals of general internal medicine as well as those in Gastroenterology and Infectious Diseases.
It has to do with long-acting stomach acid reducers that sell in the billions of doses annually, and a possible, unintended collateral susceptibility to a particular infectious disease that attacks the large intestine with explosive diarrhea and often significant organ damage.
While all of the articles in the reference list are quite important, the February 5, 2009, interchange of letters to the editor of the New England Journal of Medicine , by Baierlein & Wistop; Coulter; Della-Torre, Dagna & Saporiti, commenting on a review of Clostridium difficile by Kelly & Lamont (2008), and the response of Kelly & Lamont to these gets you to the crux of the story the fastest.
This debate has multiple propositions:
First, is there proof that the long-term use (more than a year) of proton pump inhibitors (hereafter PPIs) such as the very well selling over-the-counter Prilosec™, and the prescription brands Nexium™, and Prevacid™ change the pH of the stomach to such a state of reduced acidity that they allow for the spores of Clostridium difficile and its resulting syndrome, hereafter CDAD) to survive being ingested, allowing them to pass into the colon where they often wreak havoc?
Second, even if this is the case, what measures, if any, apart from ceasing the use of PPI would reduce the spread, duration, or severity of CDAD?
Third, even if this side effect of PPIs is a major contributing or causative factor of CDAD, would the long term Quality of Life (hereafter QOL) of patients that are on PPIs, be so poor without them, that an informed decision might still be made by the physician and the patients to continue taking them, despite the somewhat increased risk of CDAD?
Who Uses Proton Pump Inhibitors & Why?
The profile of PPI users is dominated by middle-aged overweight adults , a good percentage of whom are smokers or former smokers. Men outnumber women. Increase in users ascends with each passing decade; users in their 50 outnumber those in their 40s; users in their 60s outnumber those in their 50s. The success of PPIs in symptomatic relief is astonishing with well over 90% satisfaction, even with the old pioneer over-the-counter versions, like Prilosec™.
The most common reason patients take PPIs is GERD, GastroEsophageal Reflux Disease. This is a condition where stomach acids volcanicaly erupt up the esophagus, giving the patient a sense of severe heartburn.
The degree of symptomatology and the frequency of recurrence , plus the relative ineffectiveness of more typical over-the-counter antacids, and even of intermediate strength agents like famotidine and ranitidine, tends to bring the patient to the doctor, asking for relief.
Historically, the physician scoped the esophagus down to the stomach and looked for lesions or strictures, particularly those associated with the precancerous condition known as Barret’s strictures or Barrett’s syndrome (one of whose symptoms is actually a shortened, contracted esophagus) Without treatment with PPIs, about 10% of these cases will turn into esophageal cancers, and these have a high degree of mortality, within a year or two.
Other reasons for taking PPIs include their role as an offsetting factor for those taking NSAIDS (Non-Steroidal AntInflammmatory DrugS ) or other medications to control pain, which have the known side effect of causing ulcers or other GI bleeding when taken in large amounts, or over long periods.
PPIs also serve as part of a drug cocktail to combat Helicobacter ulcers, by offsetting the gastric effects of antibiotics, that are used to knock out the Heliobacter bacterium, and even in some cases of peptic, stress ulcers those without bacterial involvement.
A rather less common condition, known as the Zollinger-Ellison Syndrome, is caused by cancer in the pancreas and related areas of the jejunum. This disease has the collateral effect of stomach hyperacidity, which in addition to tumor removal , can be offset by PPIs.
What is CDAD and Who Gets It?
CDAD was the topic of this blog on August 28, 2008, under the the title: “Tres Difficile: Growing Concern with Clostridium difficile and Other Toxin Producing Bacteria.”
In summary, CDAD is caused by a number of endotoxic bacteria, some producing toxin A, others B or E, and some two and perhaps three toxins at once.
There is some evidence that CDAD can result from an overabundance of naturally occurring populations of these bacteria in the colon, or that CDAD can result from ingesting CD spores in the environment, usually through food handling.
The bacterial toxins cause the death of some cells lining the colon, and damage the protective mucus-producing cells in particular.
The effect is a reduction in mucus production and an increase in cellular disintegration, allowing bleeding by underlying vessels into the colonic lumen.
This shift from mucus production to internal bleeding favors the further multiplication of these bacteria, because they eat the disintegrating protein fragments or peptides that result.
With further multiplication of bacteria, the cycle gets worse and worse. Bloody diarrhea with an increasing debilitating effect on the patient is the result.
An increasing number of antibiotics have proved ineffective and today only two appear to have much success: metronidazole and if that fails, vancomycin.
There is a shift in thinking as to who was most susceptible to CDAD. Before, it was almost always the institutionalized elderly. Nowadays, it is almost any adult that has been hospitalized and had surgery, chemotherapy, or was otherwise treated with antibiotics for some time prior to the CDAD outbreak.
But some CDAD outbreaks appear seemingly out of nowhere and do not involve people with a particular known predisposition. While death is somewhat unusual in those under 60, an overall mortality rate in the mid-to-high single digits, is not unheard of in some outbreaks.
Is it a Sure Thing That PPIs Cause CDAD?
There is no direct evidence that PPIs are the direct cause of the multiplication of pre-existing populations of CDAD-causing bacteria, nor is there any smoking gun that points to their being the source of the bacterial spores that can be eaten and which will then multiply and produce the diarrheal disease.
There are now however, well over 20 studies that implicate statistically the drop in stomach acidity caused by PPIs with subsequent development of CDAD. This is particularly true with in–house patients and nursing home residents who had long been on PPIs.
But an even stronger statistical correlation remains the fact that the majority of people who developed CDAD were on some antibiotics or had an invasive procedure prior to their CDAD symptoms.
There is further a high percentage, 20%-40% of patients who develop CDAD, who were not on PPIs, nor on any other acid-reducing prescription and over-the-counter medications.
What Strategies Apart From Discontinuance Of PPIs Might Reduce CDAD?
CDAD-related spores are indeed tough. Neither alcohol-based wipes or hand cleaners, not do soap and water of themselves kill them. Wearing vinyl gloves reduces chances of cross-contamination, and it turns out that vigorous scrubbing action using soap and water or other cleaners tends to remove the spores mechanically.
To counter the argument that too many PPIs are being taken , or being prescribed or recommended too liberally, is the argument that the numbers, amounts, and lengths of time that antibiotics are used are likely even more pertinent.
This is a strength of the colonic ecological disruption argument of the causation of CDAD: So many healthy, beneficial microorganisms are being killed that almost all that’s left are the hard-to-kill, and suddenly almost-without-competition, CDAD bacteria, which are having a field day.
This idea is not without some basis clinically. Infants have high populations of C.diff. bacteria, but do not often develop CDAD.
Is this because the healthy bacteria simply keep them in check until they themselves are wiped out by an injudicious overuse of antibiotics, or alternatively, as has been suggested, C.diff. requires the presence within the colon of toxin receptors that do not appear to be developed until adulthood.
The Crux: Will a Personal Decision to Continue PPIs Cause a Public Health Crisis by Allowing the Fomenting of a Community Outbreak of CDAD?
This argument is based on two premises:
The first that the patient, in consultation with his or her physician, can decide for themselves, whether or not to continue to take PPIs. If both parties to that discussion are well-satisfied with the risk-benefit ratio, then taking PPIs is no one else’s business. Furthermore, since no clear cut causal link of taking PPIs and CDAD exists but only a statistical association, no public health argument should be allowed to hold sway.
But the second premise is that there is getting to be too much evidence of some link, even if not a causal one, and things like vaccination and quarantine programs have been based on a lot less. CDAD is getting more frequent and more damaging all the time, and everything should be used to reduce receptivity to outbreaks.
A compromise position is possible: Advise for the limited time use of PPIs, or the long-term use of PPIs, but only by that small minority that seem most at risk of Barret’s, or which has Zollinger-Ellison.
But the Quality of Life scores of those millions and millions on PPIs is currently very strong, and the number of deaths attributed to the cancers which PPIs prevents is probably greater than the number of deaths caused by CDAD, not that CDAD is unimportant.
It remains still incumbent on PPIs critics to prove that taking PPIs put the whole community at risk of CDAD susceptibility, as opposed to leaving tens of millions without PPIs to suffer from chronic, severe, heartburn, and possibly worse.
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